title: A rare variant in MYH6 is associated with high risk of sick sinus syndrome.
abstract: Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
authors.affiliation: deCODE Genetics, Sturlugata 8, Reykjavik, Iceland. hilma.holm@decode.is
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Hafdis Th
authors.initials: HT
authors.lastname: Helgadottir
authors.forename: Carlo
authors.initials: C
authors.lastname: Zanon
authors.forename: Olafur Th
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.forename: Jona
authors.initials: J
authors.lastname: Saemundsdottir
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.forename: Hrafnhildur
authors.initials: H
authors.lastname: Stefansdottir
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Matthiasson
authors.forename: Gu Mundur
authors.initials: GM
authors.lastname: Thorgeirsson
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Babar
authors.initials: B
authors.lastname: Parvez
authors.forename: Raafia
authors.initials: R
authors.lastname: Muhammad
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: G Bragi
authors.initials: GB
authors.lastname: Walters
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: David O
authors.initials: DO
authors.lastname: Arnar
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024722:Cardiac Myosins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006331:Heart Diseases / Q000235:genetics; D006339:Heart Rate / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007055:Iceland; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000503:physiopathology
chemical_list: C094239:MYH6 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains